Pharmacokinetics and Safety of GSK1349572

GSK1349572, marketed under the brand name TIVICAY, was approved by the U.S. Food and Drug Administration on August 12, 2013, as a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI). GSK1349572 is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients aged 12 years and older weighing at least 40 kg.

Figure1: Drug interaction of GSK1349572

Basic Introduction

GSK1349572, available commercially as Tivicay, is an antiretroviral medication used in combination with other drugs for the treatment of HIV/AIDS. It is also used for post-exposure prophylaxis to prevent potential HIV infection. GSK1349572 is administered orally. GSK1349572 is approved for use in a broad range of patients with HIV. It can be used in adults who have never received HIV treatment (treatment-naïve) and in adults who have previously received HIV treatment (treatment-experienced), including those who have previously been treated with other integrase inhibitors. GSK1349572 is also approved for use in children aged 12 years and older weighing at least 40 kg who are either treatment-naïve or treatment-experienced but have not previously used integrase inhibitor.

Background

The recent introduction of integrase inhibitors (INIs) into the HIV treatment armentarium has had a significant impact on HIV treatment. However, at present, raltegravir twice daily is the only licensed INI featuring a lower genetic barrier compared with boosted protease inhibitors. GSK1349572 represents a new INI in current development. It is a once-daily, unboosted INI with low pharmacokinetic variability and predictable exposure-response relationship. Phase IIb studies in antiretroviral-naïve patients have demonstrated non-inferiority to efavirenz-based HIV therapy. Phase II studies in INI-experienced patients show partially retained activity in vivo. Overall, the safety profile of GSK1349572 in all studies completed has been very favorable.

Pharmacokinetics

In a randomized, double-blind, placebo-controlled study, the pharmacokinetics of S/GSK1349572 were assessed in healthy volunteers through single-dose (2, 5, 10, 25, 50, 100 mg or placebo, n = 5–8 per arm) and multiple-dose dose-escalation trials, where the drug was administered as a suspension. Single-dose administration resulted in rapid absorption with a Cmax occurring at 0.5–1.25 hours post-dose, a bi-exponential decline in plasma concentration, and a terminal elimination half-life (t½) ranging from 13 to 15 hours; AUC increased proportionally from 2 to 100 mg, while Cmax exhibited slightly less than dose-proportional increases. In the multiple-dose study, volunteers received 10, 25, or 50 mg of S/GSK1349572 or placebo once daily for 10 days, showing dose-proportional increases in AUC0–t and Ct across the 10–50 mg dose range, with Cmax increases again slightly less than dose-proportional; steady state was achieved by approximately day 5, and for the 50 mg cohort, steady-state parameters included Cmax 6.16 µg/mL (coefficient of variation [CV] 15%), median Tmax 1.00 h (range: 0.50–2.00), AUC0–t 76.8 µg·h/mL (CV 19%), Cmin 1.48 µg/mL (CV 25%), and Ct 1.64 µg/mL (CV 25%), with low intersubject variability. Additionally, an evaluation of the effect of food intake in 12 healthy volunteers who received two 10-mg tablets under fasting conditions or with a 30% fat meal revealed that food consumption did not impact drug exposure. [1]

Safety and tolerability

In a randomized, placebo-controlled, double-blind, parallel-group, 10-day monotherapy Phase IIa dose-ranging study involving 35 integrase inhibitor-naïve HIV-infected individuals, GSK1349572 administered at doses of 2, 10, and 50 mg or placebo was generally well tolerated. The most common adverse events reported were diarrhea (14%), fatigue (7%), and headache (7%). Four grade 3 adverse events were observed: migraine headache (in the 50 mg group), asymptomatic elevation of lipase (10 mg group), asymptomatic triglyceride elevation (10 mg group), and night sweats (placebo group). No clinically relevant trends in adverse events, laboratory parameters, vital signs, or electrocardiogram values were observed. Additionally, a meta-analysis of six healthy subject trials and one HIV subject study involving short-term administration of GSK1349572, encompassing safety data from 183 subjects (166 receiving GSK1349572 and 17 receiving placebo), identified no trends for adverse events, serious adverse events, laboratory abnormalities, or changes in electrocardiogram values. It was concluded that no clinically significant safety signals were detected following short-term dosing of GSK1349572. [2]

Reference

[1] Lenz J C C, Rockstroh J K. S/GSK1349572, a new integrase inhibitor for the treatment of HIV: promises and challenges[J]. Expert Opinion on Investigational Drugs, 2011, 20(4): 537-548.

[2] Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers[J]. Antimicrobial agents and chemotherapy, 2010, 54: 254-258.

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